GM3 synthase gene is a novel biomarker for histological classification and drug sensitivity against epidermal growth factor receptor tyrosine kinase inhibitors in non‐small cell lung cancer-猫眼课题宝

DOI：

10.1111/j.1349-7006.2007.00578.x

发表时间：

2007-10

期刊：

Cancer Science

影响因子：

5.7

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

M. Noguchi;Tomoko Suzuki;K. Kabayama;Hiroki Takahashi;H. Chiba;M. Shiratori;S. Abe;A. Watanabe;M. Satoh;T. Hasegawa;S. Tagami;A. Ishii;M. Saitoh;Masanori Kaneko;K. Iseki;Y. Igarashi;J. Inokuchi

神经节苷脂在细胞增殖、分化、某些细胞周期阶段、脑发育和癌症恶变过程中的表达和组成发生了变化。为探讨肺癌组织中GM3合成酶、SAT-I mRNA和神经节苷脂GM3表达水平的特点，我们检测了40例手术切除的非小细胞肺癌组织中SAT-I和GM3的表达水平。腺癌组织中SAT-IMRNA的表达水平显著高于鳞癌和其他癌组织(P&lt；0.0001)。此外，在细支气管肺泡癌亚型中表达较高，而在实性和粘液型腺癌中表达较低(P分别为0.049、0.049和0.013)。为了阐明SAT-I mRNA与表皮生长因子受体(EGFR)-酪氨酸激酶(TK)抑制剂敏感性的关系，我们用8个未表达EGFR突变的腺癌细胞株进行了EGFR-TK抑制剂Gefitinib和AG1478的药物敏感性试验。Gefitinib和AG1478的IC50值随着SAT-I mRNA水平的升高而显著降低(R2分别为0.81和0.59)，代表了腺癌细胞系之间广泛的药物敏感性。为了探讨GM3增强对EGFR-TK抑制剂敏感性的可能机制，将SAT-I基因稳定地导入GM3阴性的小鼠3LL肺癌细胞克隆中，产生GM3重组克隆。我们发现GM3重组细胞的EGFR蛋白水平和对吉非替尼的敏感性增加，提示GM3参与了EGFR蛋白的周转。因此，人们期望通过检测非小细胞肺癌患者肺活检标本中SAT-I mRNA的表达水平，可以为合理使用EGFR-TK抑制剂建立更好的病理鉴定和个体化化疗策略。(《癌症科学》2007；98：1625-1632)

Expression of gangliosides and alterations in their composition have been observed during cell proliferation and differentiation and in certain cell cycle phases, brain development and cancer malignancy. To investigate the characteristics of GM3 synthase, SAT‐I mRNA and ganglioside GM3 expression levels in lung cancer, we examined the expression levels of SAT‐I mRNA as well as GM3 in 40 tumor tissues surgically removed from non‐small cell lung cancer patients. Adenocarcinoma tissues expressed SAT‐I mRNA levels that were significantly higher than those of squamous and other carcinomas (P < 0.0001). Moreover, the SAT‐I mRNA levels were high in the bronchioalveolar carcinoma subtype and low in the solid and mucin subtypes of adenocarcinomas (P = 0.049, 0.049 and 0.013, respectively). To clarify the relationship between SAT‐I mRNA and epidermal growth factor receptor (EGFR)‐tyrosine kinase (TK) inhibitor sensitivity, we carried out drug sensitivity tests for the EGFR‐TK inhibitors gefitinib and AG1478 using eight adenocarcinoma cell lines expressing no EGFR mutations. The IC50 values for gefitinib and AG1478 decreased dramatically with increasing SAT‐I mRNA levels (R2 = 0.81 and 0.59, respectively), representing a wide range of drug sensitivities among adenocarcinoma cell lines. To explore a possible mechanism of how GM3 could enhance the sensitivity to EGFR‐TK inhibitors, the SAT‐I gene was introduced stably into a GM3‐negative clone of murine 3LL lung cancer cells to produce GM3‐reconstituted clones. We found an increase in EGFR protein levels and gefitinib sensitivity in GM3‐reconstituted cells, suggesting the involvement of GM3 in the turnover of EGFR protein. Therefore, it is highly expected that, by measuring the expression levels of SAT‐I mRNA in lung biopsy samples from non‐small cell lung cancer patients, enhanced pathological identification and individualized chemotherapeutic strategies can be established for the appropriate use of EGFR‐TK inhibitors. (Cancer Sci 2007; 98: 1625–1632)

GM3 synthase gene is a novel biomarker for histological classification and drug sensitivity against epidermal growth factor receptor tyrosine kinase inhibitors in non‐small cell lung cancer

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